Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment.
Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment.
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DOI：
10.1158/1078-0432.ccr-10-0851
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发表时间：
2010-11-15
期刊：
影响因子：
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通讯作者：
Varella-Garcia M
中科院分区：
文献类型：
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作者：
Camidge DR;Kono SA;Flacco A;Tan AC;Doebele RC;Zhou Q;Crino L;Franklin WA;Varella-Garcia M
间变性淋巴瘤激酶(ALK)重排与实验性ALK/MET抑制剂的敏感性有关，发生在3%至5%的非小细胞肺癌中。肿瘤内荧光原位杂交(FISH)的异质性已被报道。我们探索了异质性的基础，准确测定ALK FISH阳性的要求，以及利用临床和分子因素丰富测试种群的效果。对肺癌患者进行ALK和MET FISH筛查，以及EGFR和KRAS突变筛查。73例筛查患者中有13例ALK阳性。基因拷贝数的增加伴随着经典的重排。所有阳性病例均为腺癌，12例为EGFR/KRAS野生型，1例同时存在EGFR外显子20突变。未发现与MET扩增有关联。碱性磷酸酶阳性与吸烟年限相关(P=0.0004)。在没有KRAS或EGFR突变、有10年病史的腺癌中，44.8%的病例ALK阳性。ALK FISH的阳性表达具有异质性，但ALK阳性患者肿瘤区域的平均值(54%的细胞；范围为22-87%)显著高于ALK阴性患者的邻近正常组织或肿瘤/正常区域(平均5-7%)。连续的滑动场分析显示弥漫性不均一，没有局部ALK重排的证据。当计数4个或更多视野(~60个细胞)时，敏感性和特异性均为100%。瘤内碱性磷酸酶鱼类的异质性反映了技术，而不是生物学。ALK阳性患者中ALK/MET抑制剂的临床活性可能反映了ALK的活性，但不能反映MET的活性。通过组织学、EGFR/KRAS突变和吸烟状况进行预筛选，与未选择的系列相比，ALK阳性命中率显著增加。
Anaplastic lymphoma kinase (ALK) rearrangements, associated with sensitivity to an experimental ALK/MET inhibitor, occur in 3% to 5% of non-small cell lung cancers. Intratumoral fluorescence in situ hybridization (FISH) heterogeneity has been reported. We explored the heterogeneity basis, the requirements for accurately determining ALK FISH positivity, and the effect of enriching the tested population using clinical and molecular factors. Lung cancer patients were screened by ALK and MET FISH and for EGFR and KRAS mutations. Thirteen ALK-positive cases were identified from 73 screened patients. Gene copy number increases occurred together with classic rearrangements. All positive cases were adenocarcinomas, 12 were EGFR/KRAS wild-type, and 1 had a coexistent EGFR exon 20 mutation. No association with MET amplification occurred. ALK positivity was associated with <10-pack-year smoking status (P = 0.0004). Among adenocarcinomas, without KRAS or EGFR mutations, with <10-pack-year history, 44.8% of cases were ALK positive. ALK FISH positivity was heterogeneous, but mean values in tumor areas from ALK-positive patients (54% of cells; range, 22-87%) were significantly higher than in adjacent normal tissue or tumor/ normal areas from ALK-negative patients (mean, 5-7%). Contiguous sliding field analyses showed diffuse heterogeneity without evidence of focal ALK rearrangements. One hundred percent sensitivity and specificity occurred when four or more fields (~60 cells) were counted. Intratumoral ALK FISH heterogeneity reflects technique, not biology. The clinical activity of ALK/MET inhibitors in ALK-positive patients probably reflects ALK, but not MET, activity. Prescreening by histology, EGFR/KRAS mutations, and smoking status dramatically increases the ALK-positive hit rate compared with unselected series.